Immune presentation and recognition of class I MHC phosphopeptide antigens

Stones, Daniel Henry (2013). Immune presentation and recognition of class I MHC phosphopeptide antigens. University of Birmingham. Ph.D.

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Abstract

Alterations to metabolic pathways, in particular post-translational modification, are a recognised hallmark of diseases such as autoimmunity, inflammation and cancer, and potentially provide a source of altered self antigens that can stimulate immune responses. Most notably, phosphorylated peptides have emerged as a group of tumour associated antigens which can be presented by MHC molecules and recognised by T-cells, and therefore represent promising candidates for future cancer immunotherapy strategies. However, how antigen phosphorylation impacts upon antigen presentation and recognition remains unclear. During this study I demonstrated that the phosphate moiety of phosphopeptides bearing the canonical P4 phosphorylation is more structurally diverse in its binding mode than previously thought. Strikingly, two epitopes exhibited a major conformational change upon addition of the phosphate moiety, effectively creating “conformational neoantigens”. This occurred through a similar mechanism for each epitope, whereby the presence of the phosphate moiety raised the position of the P4 Serine, allowing phosphate-mediated contacts with MHC residues and distorting the conformation of the central epitope region most critical for T- cell receptor recognition. Finally, I found that recognition of phosphopeptides can be both phosphate-dependent and epitope-specific at the level of the T-cell receptor. Therefore, this study shows that phosphorylation can have a profound and diverse effect on antigen binding, epitope identity and T-cell receptor recognition. In summary, my studies suggest that phosphopeptides are not only tumour associated but also highly antigenically distinct, establishing them as attractive candidates for cancer immunotherapy strategies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):